The background of this research plan is the particular sensitivity of central neurons to decreased supply of oxygen (hypoxia/ischemia) or glucose (hypoglycemia). These pathological conditions constitute a major cause of acute neurological dysfunction associated with stroke, cardiac arrest, shock, brain concussion, insulin coma and some liver diseases. Thus, there is a major ethical, clinical and economical interest from the society to find measures to protect, prevent, or minimize brain damage associated with these insults. In this broader perspective the application represents an effort to elucidate the basic molecular mechanism underlying neuronal necrosis and their amelioration. The basis of our working hypothesis is the proposal made by Vogt and Vogt 1937, stating that the specific physico-chemical properties of certain neuronal populations make them particularly prone to these insults. We propose that the neurons are specially sensitive to these insults as a result of both specific transmitter input and transmitter receptor characteristics. We hypothesize that in the postischemic and posthypoglycemic period an imbalance prevails between the release of excitatory and inhibitory neurotransmitters and neuromodulators. This imbalance leads to a deranged metabolic and cellular homeostasis ultimately leading to cell death. In this application we propose to put the transmitter-receptor hypothesis to a thorough and detailed scrutiny. Our objective is to investigate the regional changes in the extracellular levels of amino acids, biogenic amines and noradrenaline turnover using microdialysis tecniques. We also aim to investigate receptor characteristics of the glutamate, adenosine and glycine receptors in vulnerable and resistant areas of the brain with autoradiographic techniques, and to study the effects of locally administered receptor agonists and antagonists and trophic factors on the development of ischemic and hypoglycemic damage in the hippocampus and the striatum.